The broad, long-term objectives of this proposal are the development of novel "drug-like" inhibitors that specifically prevent the interaction of nuclear receptors with their coregulating proteins through their NR box binding site and functionally block transcriptional activation by nuclear receptors. The Specific Aims of this proposal are 1) to determine which chemical scaffolds can afford small molecule inhibitors of the interaction of co-regulators with the thyroid receptor (TR), glucocorticoid receptor (GR), androgen receptor (AR) and peroxisome proliferator activated receptor y (PPARy) and which scaffolds exhibit selectivity for individual receptors; 2) to understand the molecular mechanism of inhibitor function by determining the modes of binding of active inhibitors and the structure activity relationships of scaffolds with individual receptors and among receptors; and 3) to determine how molecular selectivity of action against a particular receptor relates to functional changes in signaling by the targeted receptor and overall changes in transcriptional regulation in the cellular environment. The health relatedness of this project is that the new method of inhibiting nuclear receptor function has the potential to provide new therapies for diseases mediated by nuclear receptors which include cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of knowledge based structure, chemistry, and cell biology to rationally produce novel small molecule inhibitors of the targeted protein interaction. The methods to be used are high throughput screening, parallel chemistry, medicinal chemistry, high throughput X-ray crystallography (structural genomics), cell biology, genomics, and pharmacology to develop inhibitors.